X. Weng, L. Pan, X. Ma, W. Luo, H. Su, Z. Pei, Z. Dong, L. Liu, J. Yang, P. Gao, et al. (2026). Ketogenic diet and β-hydroxybutyrate inhibit HDAC1 to preserve vascular smooth muscle cell function in thoracic aortic aneurysm. Journal of advanced research, 80, 475-486. https://doi.org/10.1016/j.jare.2025.05.035

PubMed 40398746

[Abstract]
BACKGROUND: Thoracic aortic aneurysm (TAA) is a serious condition characterized by dilation of the thoracic aorta, often leading to aortic dissection or rupture. Current treatments involve surgical and pharmacological interventions and do not effectively address the underlying molecular mechanisms. This study explores the effects of ketogenic diet (KD) on TAA, focusing on histone deacetylase 1 (HDAC1) and vascular smooth muscle cells (VSMCs) function.

METHODS: A β-aminopropionitrile monofumarate (BAPN)-induced TAA mouse model was used. Mice were divided into groups receiving either a standard diet or KD. Additionally, β-hydroxybutyrate (BHB), a KD-derived ketone body, and parthenolide or ITSA-1 were administered. The study measured survival rates, aortic dilation, elastin degradation, VSMC contractile markers, mitochondrial function, and oxidative stress levels.

RESULTS: KD significantly improved survival rates and reduced aortic dilation and elastin degradation in the TAA mouse model. BHB also mitigated TAA development, demonstrating similar protective effects. KD and BHB were particularly effective in preserving mitochondrial function and maintaining VSMC contractile phenotype by restoring contractile marker expression. Additionally, KD and BHB significantly reduced oxidative stress levels. The addition of HDAC1 inhibitor parthenolide or HDAC agonist ITSA-1 further evaluated the protective effects of BHB against vascular damage.

CONCLUSION: Our study reveals the important roles of KD and BHB in regulating HDAC1, preserving mitochondrial function, maintaining VSMC phenotype, and reducing oxidative stress in TAA. Our findings demonstrate KD and BHB as promising therapeutic strategies for treating TAA by targeting specific molecular pathways involved in its progression. This study highlights the significance and innovation of lifestyle interventions, such as KD, in mitigating TAA by addressing its underlying molecular mechanisms.